Mycobacterium tuberculosis and other mycobacterial pathogens have reemerged as public health threats. There is an increasing incidence of drug resistant mycobacterial strains and the rate of infection of immunocompromised individuals and health care workers has escalated. Conventional TB vaccination methods have shown mixed results, leaving an urgent need for a safe and more effective vaccine. Recent research has revealed that T lymphocytes specifically recognize mycobacterial lipids presented by CD1 cell surface proteins. To develop a prophylactic or therapeutic tuberculosis vaccine, we will investigate whether M. tuberculosis mycobacterial lipids, as presented by CD1 proteins, constitute an effective vaccine in guinea pigs, the most appropriate tuberculosis small animal model. We will clone, characterize and express guinea pig CD1 genes to enable production of anti-CD1 monoclonal and polyclonal antibody reagents during Phase I. Such antibodies and cells transfected to be CD1 positive will be critical cellular and molecular tools to confirm the CD1 restricted nature and specificity of the guinea pig immune response. Phase II goals will be to identify the critical lipid component(s) of M. tuberculosis that are immunogenic in in vitro assays as well as function as effective subunit vaccines to protect guinea pigs from virulent M. tuberculosis aerosol challenge. PROPOSED COMMERCIAL APPLICATION Tuberculosis has reemerged a public health threat. Existing TB vaccines are inadequate, ineffective and/or unsafe in certain individuals. There is therefore a critical need and a significant market for an effective tuberculosis vaccine. This proposal describes how we intend to capitalize on recent research discoveries to guide identification and development of a lipid vaccine for tuberculosis.